1. Field of the Invention
The invention relates to immunotherapy. More particularly, the invention relates to the use of antigen presenting cells, in particular dendritic cells, in immunotherapy.
2. Summary of the Related Art
T lymphocytes (i.e., T cells), unlike B lymphocytes (i.e., B cells), typically recognize their target antigen only when the antigen is presented in the context of the major histocompatibility complex (MHC). Thus, to present antigen to T lymphocytes, which include T helper cells and cytotoxic T cells, the antigen must be presented in context of an MHC molecule on the surface of an antigen presenting cell.
In particular, one type of antigen presenting cell, dendritic cells, has recently become of interest in the area of cancer immunotherapy. Steinman, Annu. Rev. Immunol. 9: 271-296 (1991) teaches that dendritic cells are rare leukocytes that originate in the bone marrow and can be found distributed throughout the body. Bjork, Clinical Immunology 92: 119-127 (1999) teaches that dendritic cells receive increasing attention due to their potential inclusion as biological adjuvants in tumor vaccines. Dendritic cells express several receptors for the Fc portion of immunoglobulin IgG, which mediate the internalization of antigen-IgG complexes (ICs). In this capacity, dendritic cells are used to present tumor antigens to T cells. Avigan, Blood Reviews 13: 51-64 (1999) teaches that several approaches have been adopted to directly load tumor antigens onto dendritic cells, including the pulsing of tumor peptides onto mature dendritic cells. Timmerman et al., Annu. Rev. Med. 50: 507-529 (1999) teaches that isolated dendritic cells loaded with tumor antigen ex vivo and administered as a cellular vaccine have been found to induce protective and therapeutic anti-tumor immunity in experimental animals. European Patent No. EP0553244 describes an antigen/dual-specific binding agent complex for stimulating a response to the antigen, where the binding agent specifically binds both the antigen and a cell surface receptor on an antigen-presenting cell, but where binding of the binding agent to the cell surface receptor does not block the natural ligand for the receptor.
The mechanism of action for dendritic cell antigen presentation has also been explored. Coughlan et al., Veterinary Immunology and Immunopathology 49: 321-330 (1996) discloses that antigen uptake by dendritic cells via Fcxcex3 receptors results in functional augmentation of antigen presentation and T cell proliferation in an in vitro sheep system. Regnault et a., J. Exp. Med. 189: 371-380 (1999) teaches that Fcxcex3 receptors induce dendritic cell maturation and promote efficient MHC class I-restricted presentation of peptides from exogenous, immunoglobulin (Ig) complexed antigens in the mouse system.
Thus, there remains a need to discover methods for utilizing dendritic cells to treat human diseases. The promise of dendritic cell-based approaches to treat diseases, such as cancer, underscores the need to actually develop such approaches as effective therapeutic treatments.
The invention provides a therapeutically effective dendritic cell-based approach to the treatment of diseases associated with an antigen. The methods according to the invention comprise combining ex vivo an antigen associated with a disease and a dendritic cell binding agent specific for the antigen, with or without a dendritic cell, to provide a composition, and administering the composition to a patient having a disease associated with the antigen, wherein the composition-administered patient receives a therapeutic benefit.
Accordingly, in a first aspect, the invention provides a method for treating a patient suffering from a disease associated with an antigen, comprising administering to the patient suffering from the disease a composition comprising an antigen associated with the disease and a dendritic cell binding agent specific for the antigen, wherein the antigen is complexed to the dendritic cell binding agent and wherein the patient administered the composition receives a therapeutic benefit. Preferably, the patient is human.
In a second aspect, the invention provides a method for treating a patient suffering from a disease associated with an antigen, comprising administering to the patient a composition comprising an antigen associated with the disease, a dendritic cell binding agent specific for the antigen, and a dendritic cell autologous to the patient, wherein the patient administered the composition receives a therapeutic benefit. Preferably, the patient is a human.
In a third aspect, the invention provides a method for treating a patient suffering from a disease associated with an antigen, comprising administering to the patient suffering from the disease a composition comprising a host anti-xenotypic antibody and a xenotypic antibody specific for the antigen associated with the disease, wherein the patient administered the composition receives a therapeutic benefit.
In a fourth aspect, the invention provides a therapeutic composition comprising a purified dendritic cell binding agent that is specific for an antigen associated with a disease and the antigen associated with the disease. In preferred embodiments, binding of the dendritic cell binding agent to a receptor on a dendritic cell blocks binding of a natural ligand to the receptor. In certain embodiments of the fourth aspect of the invention, administration of the composition to a patient suffering from the disease provides the patient a therapeutic benefit. Preferably, the patient is a human. Preferably, the dendritic cell binding agent is an antibody.
In a fifth aspect, the invention provides a therapeutic composition comprising a purified dendritic cell binding agent that is specific for an antigen associated with a disease, a dendritic cell, and the antigen associated with the disease. In preferred embodiments, binding of the dendritic cell binding agent to a receptor on the dendritic cell blocks binding of a natural ligand to the receptor. In certain embodiments, administration of the composition to a patient suffering from the disease provides the patient a therapeutic benefit, wherein the dendritic cell is autologous to the patient. Preferably, the patient is human
In a sixth aspect, the invention provides a therapeutic composition comprising a purified xenotypic antibody that is specific for an antigen associated with a disease and a host anti-xenotypic antibody. In certain embodiments, administration of the composition to a patient suffering from the disease provides the patient a therapeutic benefit, wherein the dendritic cell is autologous to the patient. Preferably, the patient is human